Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs), for thyroid-stimulating hormone (TSH-R) and for free fatty acids (GPR40/FFAR1) as model 7TMRs to study their structure and function. During this year, we have studied several new aspects of the structure and function of these receptors. 1) We discovered/developed a small molecule antagonist for the human TSH-R that inhibits activation by TSH and also by thyroid-stimulating antibodies from patients with Graves hyperthyroidism. This represents a proof-of-principle that small molecule antagonists of TSH-R could be used as drugs to treat hyperthyroid patients. 2) We generated a mouse that did not express TRH-R2 and found that these mice exhibit increased depression and reduced anxiety phenotypes. These findings point to an important role of TRH-R in neuropsychiatric disorders. 3) Using homology models, we predicted residues within FFAR1 that are important for agonist recognition and receptor activation, and then showed that these predictions were correct using site-specific mutagenesis. These findings point to a new mechanism by which receptors of Class A 7TMRs may be activated. 4) We used our homology model of FFAR1 to perform virtual screening of potential low molecular weight ligands for FFAR1 and discovered novel agonists and antagonists. Based on our research into FFAR1, we were invited to contribute a review article on FFARs.